KR0156549B1 - Anti-plaque and anti-tartar dentifrices in plastic pump dispensers - Google Patents

Abstract

None.

Description

Antimicrobial Antiplaque, Anti-Cat Oral Composition

The present invention relates to antimicrobial anti-plaque anti-calcium oral compositions. More specifically, the present invention relates to polyphosphate anti-stone (i.e., anti-tartar) agents compatible with the presence of antimicrobial-enhancing agents that enhance the delivery of antimicrobial agents to the oral surface and retention on the oral surface. An oral composition containing an antimicrobial agent effective to inhibit possible plaques.

US Pat. No. 4,627,977 to Gaffar; Parran group No. 4,515,772; And Parran et al. 4,323,551, oral compositions containing various polyphosphate compounds. In the Gaffa group patent, linear molecularly dehydrated polyphosphate salts are used with fluoride ion-providing sources and synthetic linear polycarboxylate polymers to inhibit the formation of stones. In co-pending European Patent Application No. 89 200 710.5, using reduced amounts of linear molecularly dehydrated polyphosphate salts and increased amounts of synthetic linear polycarboxylate polymers with fluoride ion-providing sources, The anti-stone effect is optimized.

In the Parran companion and Parran patents, water soluble dialkali metal pyrophosphate is used alone or in admixture with sakali metal pyrophosphate.

Since stones are one of the factors causing the fascia condition, oral compositions that inhibit the formation of stones on the tooth surface are highly desirable. Thus, the reduction of stones promotes oral hygiene.

Tooth plaque is a precursor to stones. However, unlike stones, plaques may form on any part of the tooth surface, particularly including gingival edges. Thus, this is not only unobtrusive, but is associated with the development of gingivitis.

Therefore, it would be highly desirable to include antimicrobial agents that have been known to reduce plaque in oral compositions that contain anti-calcite agents. Indeed, this is described in Vinson's U.S. Pat. No. 4,022,550, wherein a compound that provides zinc ions as an anti-calculator is mixed with an antimicrobial agent that is effective in inhibiting the growth of plaque bacteria. Various antimicrobial agents are described with zinc compounds, including non-cationic compounds such as halogenated salicylates and halogenated hydroxydiphenyl ethers, as well as cationic materials such as quaternary ammonium compounds and guanides.

To date, cationic antimicrobials such as chlorhexidine, benzetonium chloride and cetyl pyridinium chloride have been the subject of most studies as antimicrobial antiplaque agents. However, they are not effective when used in combination with anionic materials such as polyphosphate anti-stones, even though they are used with zinc anti-stones. Since polyphosphate is a chelating agent and the chelating effect is already known to increase cationic antimicrobial efficacy, such inefficiencies are considered quite surprising. [See, eg, Disinfection, sterilization and Preservation, 2nd Ed., Black, 1977, Page 915) and Inhibition and Destruction of the Microbial Cell, Hugo, 1971, Page 215. In fact, the quaternary ammonium compound is present in plaque-controlled salvage solution containing pyranphosphate of US Pat. Proposed in the composition.

In view of the surprising incompatibility of polyphosphate and cationic antimicrobial agents present as anti-stones, other antimicrobial agents are not expected to be effective.

An advantage of the present invention is that certain antimicrobial agents in the linearly molecularly dehydrated polyphosphate salts, fluoride ion-providing sources, and anti-stone oral compositions containing the antimicrobial-enhancing agents are effective in inhibiting plaque formation.

Another advantage of the present invention is that a composition is provided that is effective in reducing stone formation and optimizing plaque reduction.

Another advantage of the present invention is that an anti-plaque, anti-calcium oral composition is provided that is effective in reducing the occurrence of gingivitis.

Additional advantages of the present invention will become apparent from a review of the following specification.

According to certain aspects thereof, the present invention provides an effective anti-absence amount of material comprising about 0.1 to 3% by weight of at least one linear molecularly dehydrated polyphosphate salt as an anti-calculator in an orally acceptable excipient, an effective anti An oral composition comprising an amount of plaque substantially a water-insoluble noncationic antimicrobial agent, and an antimicrobial-enhancing agent, preferably up to about 4% by weight, to enhance delivery and retention of the antimicrobial agent onto the oral surface, wherein the antimicrobial activity The weight ratio of enhancer to polyphosphate ions is typically greater than 0.72: 1 to less than 4: 1 (eg, about 1: 1 to about 3.5: 1), particularly about 1.6: 1 to about 2.7: 1, preferably about 1.7: 1 to about 2.3: 1, most preferably about 1.9: 1 to about 2.1: 1. For example, when 2% tetrasodium pyrophosphate (TSPP) is used with 2.5% antimicrobial-enhancing agent (provides about 1.3% of pyrophosphate ions), a very preferred weight ratio of about 1.9: 1 is provided.

Given the antiplaque effect, stability and combination, typical examples of particularly preferred antimicrobials are as follows:

[Halogenated Diphenyl Ether]

2 ', 4,4'-trichloro-2-hydroxy-diphenyl ether (triclosan)

2,2'-dihydroxy-5,5'-dibromo-diphenyl ether.

[Halogenated Salicylic Anide]

4 ', 5-dibromosalicylate anlide

3,4 ', 5-trichlorosalicylanilide

3,4 ', 5-tribromosalicillanilide

2,3,3 ', 5-tetrachlorosalicylanilide

3,3,3 ', 5-tetrachlorosalicylanilide

3,5-dibromo-3'-trifluoromethyl salicylate

5-n-octanoyl-3'-trifluoromethyl salicylicanilide

3,5-dibromo-4'-trifluoromethyl salicylate

3,5-dibromo-3'-trifluoro methyl salicylicanilide (fluorophene)

[Benzoic acid ester]

Methyl-p-hydroxybenzoic acid ester

Ethyl-p-hydroxybenzoic acid ester

Propyl-p-hydroxybenzoic acid ester

Butyl-p-hydroxybenzoic acid ester

[Halogenated Carbanilide]

3,4,4'-trichlorocarbanilide

3-trifluoromethyl-4,4'-dichlorocarvanide

3,3,4'-trichlorocarbanilide

Phenolic compounds (including phenols and their analogs, mono- and poly-alkyl and aromatic halo (eg, F, Cl, Br, I) -phenols, resorcinol and catechol and derivatives thereof and bisphenolic compounds). Phenolic compounds include, inter alia, the following compounds:

[Phenols and their homologues]

phenol

2 methyl-phenol

3-methyl-phenol

4-methyl-phenol

4 ethyl-phenol

2, 4-dimethyl-phenol

2, 5-dimethyl-phenol

3,4-dimethyl-phenol

2, 6-dimethyl-phenol

4-n propyl-phenol

4-n butyl-phenol

4-n amyl-phenol

4-tert-amyl-phenol

4-n-hexyl-phenol

4-n-heptyl-phenol

2-methoxy-4- (2-propenyl) -phenol (eugenol)

2-isopropyl-5-methyl-phenol (thymol)

[Mono and poly-alkyl and aralkyl halophenols]

Methyl-p-chlorophenol

Ethyl-p-chlorophenol

n-propyl-p-chlorophenol

n-butyl-p-chlorophenol

n-amyl-p-chlorophenol

Secondary-amyl-p-chlorophenol

n-hexyl-p-chlorophenol

Cyclohexyl-p-chlorophenol

n-heptyl-p-chlorophenol

n-octyl-p-chlorophenol

o-chlorophenol

Methyl-o-chlorophenol

Ethyl-o-chlorophenol

n-propyl-o-chlorophenol

n-butyl-o-chlorophenol

n-amyl-o-chlorophenol

Tert-amyl-o-chlorophenol

n-hexyl-o-chlorophenol

n-heptyl-o-chlorophenol

p-chlorophenol

o-benzyl-p-chlorophenol

o-benzyl-m-methyl-p-chlorophenol

o-benzyl-m, m-dimethyl-p-chlorophenol

o-phenylethyl-p-chlorophenol

o-phenylethyl-m-methyl-p-chlorophenol

3-methyl-p-chlorophenol

3,5-dimethyl-p-chlorophenol

6-ethyl-3-methyl-p-chlorophenol

6-n-propyl-3-methyl-p-chlorophenol

6-iso-propyl-3-methyl-p-chlorophenol

2-ethyl-3,5-dimethyl-p-chlorophenol

6-Second Butyl-3-methyl-p-chlorophenol

2-iso-propyl-3,5-dimethyl-p-chlorophenol

6-diethylmethyl-3-methyl-p-chlorophenol

6-iso-propyl-2-ethyl-3-methyl-p-chlorophenol

2-secondary amyl-3,5-dimethyl-p-chlorophenol

2-diethylmethyl-3,5-dimethyl-p-chlorophenol

6-Second Octyl-3-methyl-p-chlorophenol

p-bromophenol

Methyl-p-bromophenol

Ethyl-p-bromophenol

n-propyl-p-bromophenol

n-butyl-p-bromophenol

n-amyl-p-bromophenol

Secondary-amyl-p-bromophenol

n-hexyl-p-bromophenol

Cyclohexyl-p-bromophenol

o-bromophenol

Tert-amyl-o-bromophenol

n-hexyl-o-bromophenol

n-propyl-m, m-dimethyl-o-bromophenol

2-phenyl phenol

4-chloro-2-methyl phenol

4-chloro-3-methyl phenol

4-chloro-3,5-dimethyl phenol

2,4-dichloro-3,5-dimethyl phenol

3,4,5,6-tetrabromo-2-methylphenol

5-methyl-2-pentylphenol

4-isopropyl-3-methylphenol

5-chloro-2-hydroxydiphenyl methane

[Resorcinol and its derivatives]

Resorcinol

Methyl-resorcinol

Ethyl-resorcinol

n-propyl-resorcinol

n-butyl-resorcinol

n-amyl-resorcinol

n-hexyl-resorcinol

n-heptyl-resorcinol

n-octyl-resorcinol

n-nonyl-resorcinol

Phenyl-resorcinol

Benzyl-resorcinol

Phenylethyl-resorcinol

Phenylpropyl-resorcinol

p-chlorobenzyl-resorcinol

5-chloro-2,4-dihydroxydiphenyl methane

4'-chloro-2,4-dihydroxydiphenyl methane

5-bromo-2,4-dihydroxydiphenyl methane

4'-bromo-2,4-dihydroxydiphenyl methane

[Bisphenolic Compound]

Bisphenol A

2,2'-methylene bis (4-chlorophenol)

2,2'-methylene bis (3,4,6-trichlorophenol) (hexachlorophene)

2,2'-methylene bis (4-chloro-6-bromophenol)

Bis (2-hydroxy-3,5-dichlorophenyl) sulfide

Bis (2-hydroxy-5-chlorobenzyl) sulfide

The antimicrobial agent is in an effective amount of antiplaque in the oral composition, typically from about 0.01 to 5% by weight, preferably from about 0.03 to 1% by weight, very preferably from about 0.25 to 0.5% by weight, most preferably from about 0.25 to 0.35% by weight. exist. The antimicrobial agent is substantially water-insoluble, meaning that its solubility may be less than about 1% by weight and even less than about 0.1% by weight in water at 25 ° C. If ionizable groups are present, solubility is measured at a pH at which no ionization occurs.

Preferred halogenated diphenyl ether is triclosan. Preferred phenolic compounds are phenol, 2,2'-methylene bis (4-chloro-6-bromophenol), thymol and eugenol. The most preferred antimicrobial antiplaque compound is triclosan. Triclosan is disclosed in US Pat. No. 4,022,880 as described above in German Patent Specification 35 32 860 as an antimicrobial agent with an anti-calculator providing zinc ions. It is also formulated to contain a layered liquid crystal surfactant phase, having a layered clearance of less than 6.0 nm, and may optionally contain the zinc salt of Lane et al. Published European Patent Application No. 0161898. In toothpastes containing zinc citrate trihydrate of Saxton's published European patent application No. 0161899, it is disclosed as an anti-plaque agent.

Linear molecularly dehydrated polyphosphate salts which act as anti-calculators herein are known and generally are in whole or in part neutralized water soluble alkali metals (eg, potassium and preferred sodium) or ammonium salts and any thereof Used in the form of a mixture. Representative examples include sodium hexametaphosphate, sodium tripolyphosphate, disodium diacid, trisodium monoacid and tetrasodium pyrophosphate, the corresponding potassium salts, and the like. Linear polyphosphate corresponds to (NaPO ₃ ) _n , where n is about 2 to 125. In the present invention, they are used in the oral composition at about 0.1 to 3 weight percent, typically 1 to 25 weight percent, more typically 1.5 to 2 weight percent. When n is at least _{3 in} (NaPO ₃ ) _n , the polyphosphate is glassy.

Particularly preferred anti-stones are tetraalkali metal pyrophosphates comprising mixtures thereof, such as tetrasodium pyrophosphate, tetrapotassium pyrophosphate and mixtures thereof. Accordingly, the oral composition is substantially free of sodium pyrophosphate or polyphosphate free from the combination of tetrasodium pyrophosphate and tetrasodium pyrophosphate, where the ratio of potassium to sodium pyrophosphate is at least 3: 1 or 3: 1. And may contain anti-stones. Particularly effective are anticalculants comprising about 2% tetrasodium pyrophosphate by weight in oral compositions.

Antimicrobial-enhancing agents (AEAs) that enhance the delivery and retention of the antimicrobial agent to the oral surface are from about 0.05% to about 4%, preferably from about 0.1% to about 3%, more preferably about 0.5% by weight in the oral composition. It is used in an amount effective to attain such enhancement in the range of weight percent to about 2.5 weight percent.

The AEA may be a simple compound, preferably a polymerizable monomer, more preferably a polymer. The latter term is here a very broad term including, for example, oligomers, homopolymers, copolymers of two or more monomers, ionomers, block copolymers, graft copolymers, crosslinked polymers and copolymers and the like. AEA may be natural or synthetic, and may be water-insoluble or preferably water (saliva) water soluble or water-expandable (hydratable, hydrogel forming). Its (weight) average molecular weight is about 100 to about 1,000,000, preferably about 1,000 to about 1,000,000, more preferably about 2,000 or 2,500 to about 250,00 0 or 500,000.

AEA is usually at least one transfer-enhancer (which is preferably acidic such as sulfonic acid, phosphinic acid or more preferably phosphonic acid or carboxylic acid or salts thereof such as alkali metals or ammonium) and at least one organic retention-enhancing Groups, preferably transfer-enhancing and retention-enhancing groups, wherein the latter group preferably has the general formula— (X) _n —R, wherein X is O, N, S, SO, SO ₂ , P, PO Or Si and R is hydrophobic alkyl, alkenyl, acyl, aryl, alkaryl, aralkyl, heterocyclic or their inert-substituted derivatives, n is zero or one or more than one. Such inert-substituted derivatives are usually non-hydrophilic and have a substituent on R such as halo (ie, Cl, Br) that does not significantly interfere with the required action of AEA, which enhances delivery and retention of the antimicrobial agent to the oral surface. , I) and carbo and the like. Examples of such retention-enhancers are shown in the table below.

As used herein, a delivery-enhancer refers to the delivery of an antimicrobial agent to the surface by attaching (or carrying antimicrobial) AEA to the oral (eg, teeth and gums) surface, or by being significantly cohesive, cohesive or otherwise binding. . Organic retention-enhancers, which are generally hydrophobic, promote the retention of the antimicrobial agent to the AEA and indirectly on the oral surface by attaching or otherwise binding the antimicrobial agent to the AEA. In some cases, the attachment of the antimicrobial agent is brought about through physical confinement by the AEA, especially when the AEA is a crosslinked polymer, this structure inherently provides an increased site for such confinement. The presence of high molecular weight, more hydrophobic crosslinking sites in the crosslinked polymer further promotes physical confinement of the antimicrobial agent to or by the crosslinked AEA polymer.

Preferably, the AEA is at least one carbon atom and preferably at least one directly or indirectly stretched monovalent transfer-enhancer and at least one atom bonded to an atom in the chain, preferably overlapping, closer or less preferably, to the carbon It is an anionic polymer composed of chains or main chains containing repeating units, each preferably containing a monovalent retaining-enhancer, directly or indirectly. Less preferably, the polymer may comprise transfer-enhancers and / or retention-enhancers and / or other divalent atoms or groups as moieties added to the carbon atoms and instead as bonds or crosslinks in the polymer chain.

Any example of an AEA disclosed herein that does not include both a delivery-enhancer and a retention enhancer is known in chemically known manner to obtain a preferred AEA containing all of these groups, preferably containing a plurality of each of said groups. It will be understood that it may be modified, and preferably modified. In the case of the preferred polymeric AEA, the repeating unit in the polymer chain or main chain containing the acidic delivery enhancer contains at least about 10%, preferably at least about 50% by weight of the polymer, to maximize the presence and delivery of the antimicrobial agent to the oral surface. More preferably at least 80 wt% to 95 wt% or up to 100 wt%.

According to a preferred embodiment of the invention, the AEA consists of a polymer containing repeating units in which at least one phosphonic acid transfer-enhancer is bonded to at least one carbon atom in the polymer chain. An example of such an AEA is poly (vinylphosphonic acid) which contains units of the general formula (I) but does not contain a retention-enhancer:

However, the latter type of group will be present in poly (1-phosphonopropene) having units of the general formula (II) below.

Preferred phosphonic acid containing AEAs for use herein are those of the general formula (III), wherein Ph is phenyl, with a phenyl retention-enhancer and a phosphonic acid transfer-enhancer bound near a carbon atom in the chain:

의 단위를 함유하는 폴리(베타스티렌포스폰산), 또는, 상기 일반식(I)의 단위와 함께 교호 또는 무작위로 결합되는 상기 일반식(III)의 단위를 가지는 염화 비닐 포스포닐과 베타스티렌 포스폰산의 공중합체, 또는, 전달- 및 보유-증진기가 사슬에 겹치게 결합되는, 일반식 (IV):

Poly (betastyrene phosphonic acid) containing units of, or vinylphosphonyl chloride and betastyrene phosphonic acid having units of the general formula (III) which are alternately or randomly combined with the units of the general formula (I). Of formula (IV) wherein a copolymer of or a transfer- and retention-enhancer is superimposed on a chain:

의 단위를 함유하는 폴리(알파스티렌포스폰산)이다.

It is poly (alpha styrene phosphonic acid) containing the unit of.

These styrene phosphonic acid polymers and their copolymers with other inert ethylenically unsaturated monomers usually have a molecular weight of about 2,000 to about 30,000, preferably about 2,500 to about 10,000. Such inert monomers do not significantly interfere with the intended action of any copolymer used herein as AEA.

Other phosphonic acid-containing polymers are for example general formula (V):

(여기서, n은 예컨대 정수이거나, 중합체가 약 3,000의 분자량을 제공할 정도의 값을 가진다)의 단위를 가지는 포스폰화 에틸렌; 및 일반식(VI):

의 단위를 가지는 나트륨 폴리(부텐-4,4-디포스포네이트) 및 일반식 (VII):

의 단위를 가지는 폴리(알릴 비스(포스포노 에틸아민)을 포함한다. 폴리(알릴포스포노 아세테이트), 포스폰화 폴리메타크릴레이트 등과 같은 다른 포스폰화 중합체 및 EP 특허 제 0321233 호에 개시된 겹쳐진 디포스포네이트 중합체가 상기-정의된 유기 보유-증진기를 함유하거나 함유하도록 개질된다면 본원에서 AEA로서 사용될 수 있다.

Phosphonated ethylene having units of (where n is, for example, an integer or has a value such that the polymer provides a molecular weight of about 3,000); And general formula (VI):

Sodium poly (butene-4,4-diphosphonate) having units of and of formula (VII):

Poly (allyl bis (phosphono ethylamine)) having units of: other phosphonated polymers such as poly (allylphosphono acetate), phosphonated polymethacrylate and the like and overlapped diphosphonates disclosed in EP Patent No. 0321233 Polymers can be used as AEA herein if they are modified to contain or contain an above-defined organic retention-enhancer.

In an aspect of the invention, the oral composition contains an orally acceptable excipient, at least one functional group that enhances the delivery of the antimicrobial effect and at least one organic group that enhances the retention of the antimicrobial effect, and has an average molecular weight of about 1,000 to about Agents effective in enhancing the antimicrobial effect of the 10,000,000 antimicrobial agent, wherein the agent containing the group is free or substantially free of ammonium synthetic anionic linear polymer polycarboxylate salts or water soluble alkali metals having a molecular weight of about 1,000 to 1,000,000, And polyphosphate anti-calcite agents such as mixtures of potassium and sodium salts having a potassium: sodium ratio of less than about 3: 1 (eg, about 0.37 to about 1.04: 1) in the oral composition.

According to another preferred embodiment, the AEA also comprises a synthetic anionic polymerized polycarboxylate which is an inhibitor of alkaline phosphatase enzyme. Synthetic anionic polymerized polycarboxylates and their various cationic fungicides, anti-stones with zinc and magnesium as such, for example, US Pat. No. 3,429,963 to Shedlovsky; Gaffa, U.S. Patent No. 4,152,420; US Patent No. 3,956,480 to Decatur Group; US Pat. No. 4,138,477 to Gaffa; And US Pat. No. 4,183,914 to Gaffa Group. However, only the disclosure of Gappa et al. US Pat. No. 4,627,977 describes the use of such polycarboxylates in combination with compounds that provide a source of fluoride ions for inhibiting saliva hydrolysis of pyrophosphate anti-calcite agents. The synthetic anionic polymerized polycarboxylates disclosed in this patent act as AEA in the compositions and methods of the present invention when modified to contain or contain retention-enhancing groups as defined above, and the disclosure should be understood to be incorporated herein by reference. .

These synthetic anionic polymerized polycarboxylates are often their free acids or preferably partially or more preferably fully neutralized water soluble or water-expandable (hydratable, gel / forming) alkali metals (eg potassium and preferably sodium). Or in the form of ammonium salts. Preference is given to 1: 4 to 4: 1 copolymers of maleic anhydride or acid and other polymerizable ethylenically unsaturated monomers, preferably methyl vinyl ether / maleic anhydride having a molecular weight (M.W.) of about 30,000 to about 1,000,000. These copolymers are for example Gantrez such as AN 139 (M.W. 500,000), AN 119 (molecular weight 250,000); And preferably S-97 pharmaceutical grade (molecular weight 70,000) of GAF Corporation.

Other AEA-functional polymerized polycarboxylates containing or modified to contain retention-enhancing groups include maleic anhydride and ethylacrylate, hydroxyethyl methacrylate, N-vinyl-2-pyrrolidone, or ethylene (the latter). Is a 1: 1 copolymer of, for example, Monsanto EMA No. 1103 (molecular weight 10,000) and EMA grade 61) and acrylic acid and methyl or hydroxyethyl methacrylate, methyl or ethylacrylate, isobutyl vinyl ether Or those disclosed in the aforementioned US Pat. No. 3,956,480, such as 1: 1 copolymers of N-vinyl-2-pyrrolidone.

The additional functional polymerized polycarboxylates disclosed in the above-mentioned U.S. Pat. Nos. 4,138,477 and 4,183,914 modified or containing retention-enhancing groups include maleic anhydride and styrene, isobutylene or ethyl vinyl ether, Copolymers of polyacrylic acid, polyitaconic acid and polymaleic acid and sulfoacrylic oligomers having a molecular weight as low as 1,000, commercially available as Uniroyal ND-2.

Retention-promoter-containing olefinic or ethylenically unsaturated carboxylic acids containing an activated carbon-to-carbon olefinic double bond and at least one carboxyl group, ie at the α-β position relative to the carboxyl group or as part of a terminal methylene group Acids containing olefinic double bonds that readily function in the polymerization reaction because they are present in the monomer molecule are generally suitable. Examples of the acid include acrylic acid, methacrylic acid, ethacrylic acid, α-chloroacrylic acid, crotonic acid, β-acryloxy propionic acid, sorbic acid, α-chlorosorbic acid, cinnamic acid, β-styrylacrylic acid, muconic acid and itaconic acid. , Citraconic acid, mesaconic acid, glutamic acid, aconic acid, α-phenylacrylic acid, 2-benzyl acrylic acid, 2-cyclohexyl acrylic acid, angelic acid, umbelic acid, fumaric acid, maleic acid and anhydrides. Other olefinic monomers copolymerizable with the carboxylic acid monomer include vinyl acetate, vinyl chloride, dimethyl maleate and the like. The copolymer usually contains sufficient carboxylic acid salt groups to be water soluble.

US Patent No. 3,980,767 to Choown; US Pat. No. 3,935,306 to Roberts group; US Pat. No. 3,919,409 to Parla; Useful herein are the so-called carboxyvinyl polymers disclosed herein as toothpaste components in US Pat. No. 3,911,904 to Harrison and US Pat. No. 3,711,604 to Colonney. These are Bie. V. Commercially available under the trade names Carbopol 934, 940 and 941 from BVGoodrich, these products are crosslinked with about 0.75% to about 2.0% polyallyl sucrose or polyallyl pentaerythritol as crosslinking agent. Essentially composed of colloidal water-soluble polymers of polyacrylic acid, the crosslinked structure and bonding provide the desired retention enhancement with hydrophobic and / or physical confinement of antibacterial agents and the like. Polycarbophil is somewhat similar to polyacrylic acid crosslinked to less than 0.2% divinyl glycol (low proportions, molecular weight and / or hydrophobicity of these crosslinkers tend to provide reduced retention or not retention enhancement). 2,5-dimethyl-1,5-hexadiene is an example of a more effective retention-enhancing crosslinker.

Synthetic anionic polymeric polycarboxylate components are mostly hydrocarbons having halogen and O-containing substituents and bonds present in, for example, esters, ethers and OH groups, which are up to about 4% (usually at least about 0.05%) in the present composition. Usually applied as an approximate weight.

AEA may also include natural anionic polymerized polycarboxylates containing retention-enhancing groups. Carboxymethyl cellulose and other binders, gums and film-forming agents without the above-defined delivery-enhancing and / or retention-enhancing groups are inefficient as AEA. Examples of AEAs containing phosphinic acid and / or sulfonic acid transfer enhancers are required on 1 or 2 (or 3) carbon atoms, for example by organic retention-enhancers having the general formula-(X) _n -R above. Mention may be made of polymers and copolymers containing units or moieties derived from the polymerization of substituted vinyl or allyl phosphine acids and / or sulfonic acids. Copolymers of one or more inert polymerizable ethylenically unsaturated monomers as described above for mixtures of these monomers and their functional synthetic anionic polymeric polycarboxylates can be used. In these and other polymerization AEAs, typically only one acidic transfer-enhancer is bonded to any given carbon or other atom in the polymer backbone or branch. Polysiloxanes modified to contain or contain pendant transfer-enhancers and retention enhancers can also be used herein as AEA. Also effective herein as AEA are ionomers modified to contain delivery- and retention-enhancers. Ionomers are described in the Kirk Othmer Encyclopedia of Chemical Technology, 3rd Edition, Addendum, pages 546-573 of John Willy Sons, Inc., 1984, incorporated herein by reference. Also effective herein as AEA, are proteins, such as collagen, poly (arginine) and other polymerized amino acids, polyesters including proteinaceous materials, and polyurethanes, provided they contain or have been modified to contain retention-enhancers Synthetic and natural polyamides.

When the oral preparation is prepared by initially dissolving the antimicrobial agent and polyphosphate in the humectant and the surfactant and gradually increasing the addition of AEA, in particular polycarboxylate, the solution can be cleared and characterized by microemulsion. As the amount of polycarboxylate is increased to contain at least about 2.2% by weight of polycarboxylate of the complete oral formulation, the solution may become cloudy and be characterized as a macroemulsion. In the macroemulsion type composition, the antiplaque effect of the antimicrobial agent appears to be optimized.

A preferred weight ratio of medicament to a substantially water-insoluble noncationic antimicrobial agent to polyphosphate anti-calcite agent is greater than about 0.72: 1 to less than about 4: 1 (eg, about 1: 1 to about 3.5: 1), in particular about 1.6: 1 to about 2.7: 1.

In order to optimize the anti-stone effect of the oral composition, it is desirable to have an inhibitor for the enzymatic hydrolysis of polyphosphate. The medicament comprises a fluoride ion source in an amount sufficient to provide 25 ppm to 5,000 ppm of fluoride ions, and 3% or 3% synthetic anionic polymerized polycarboxylate having a molecular weight of about 1,000 to about 1,000,000, preferably about 30,000 to about 500,000. The above is the following.

Fluoride source or fluorine-providing components as acid phosphatase and pyrophosphatase enzyme inhibitor components are known in the art as anti cavities. These compounds may be slightly soluble in water or may be completely water soluble. They are characterized by their ability to release fluoride ions in water and freedom from unwanted reactions with other compounds of the oral formulation. These materials include sodium fluoride, potassium fluoride, ammonium fluoride, copper fluorides such as cuprous fluoride, zinc fluoride, barium fluoride, sodium fluorosilicates, ammonium fluorosilicates, sodium fluorozirconates, ammonium fluorozirconates, Inorganic fluoride salts such as soluble alkali metal, alkyl earth metal salts such as sodium monofluorophosphate, aluminum mono- and difluorophosphate, and sodium calcium fluoride phosphate. Preference is given to tin fluorides such as alkali metals and sodium fluoride and first tin, sodium monofluorophosphate (MFP) and mixtures thereof.

The amount of fluorine-providing compound depends to some extent on the form of the compound, its solubility, and the form of the oral formulation, but usually should be a non-toxic amount of about 0.005 to about 3.0% in the formulation. In toothpaste formulations, such as dental gels, toothpastes (including creams), powdered toothpastes or dental tablets, it is considered satisfactory for the amount of the compound to release F ions of about 5,000 ppm or less of the formulation's weight. Although an appropriate minimum amount of the compound can be used, it is preferred that enough compounds be used to release fluoride ions from about 300 to 2,000 ppm, more preferably from about 800 to about 1,500 ppm.

Typically, in the case of alkali metal fluorides, the component is present at up to about 2% by weight, preferably from about 0.05% to 1%, based on the weight of the formulation. In the case of sodium monofluorophosphate, the compound may be present in about 0.1 to 3%, more typically about 0.76%.

In oral preparations, such as saliva liquor, sugar-containing tablets and chewing gums, fluorine-providing compounds are typically present to a degree sufficient to release fluoride ion weights of about 500 ppm or less, preferably 25 to 300 ppm. Generally from about 0.005 to about 1.0 weight percent of said compound is present.

In a very preferred form of the invention, the oral composition may be a substantial liquid, such as salvage or flushing fluid. In such formulations, excipients are typically water-alcohol mixtures containing moisturizers as described below. Usually, the weight ratio of water to alcohol is from about 1: 1 to about 20: 1, preferably from about 3: 1 to 10: 1, more preferably from about 4: 1 to about 6: 1. The total amount of water-alcohol mixture in this type of formulation is typically from about 70 to about 99.9 weight percent of the formulation. The alcohol is typically ethanol or isopropanol. Ethanol is preferred.

Other formulations of the present invention and the pH of the liquid are generally about 4.5 to about 9 and typically about 5.5 to about 8. Preferred pH is from about 6 to about 8.0. It is noteworthy that the compositions of the present invention can be applied orally below pH 5, without substantially demineralizing or otherwise damaging the tooth enamel. The pH can be adjusted with acids (e.g. citric acid or benzoic acid) or with a base (e.g. sodium hydroxide), or (sodium citrate, benzoate, carbonate or bicarbonate, disodium hydrogen phosphate, sodium dihydrophosphate, etc.). Can be buffered).

In certain other preferred forms of the invention, the oral composition may be in a state such as a substantially solid or paste, such as powdered toothpaste, dental tablets or toothpaste (ie, creamy toothpaste or gel toothpaste). Excipients in oral formulations such as solids or pastes usually include acceptable abrasives for the tooth. Examples of abrasives include water-insoluble sodium metaphosphate, potassium metaphosphate, tricalcium phosphate, calcium dihydrate phosphate, anhydrous dicalcium phosphate, calcium pyrophosphate, magnesium orthophosphate, trimagnesium phosphate, calcium carbonate, alumina hydroxide, calcined alumina, aluminum Silicates, zirconium silicates, silicas. Bentonite, and mixtures thereof. Other suitable abrasives include particulate thermoset resins such as melamine-, phenol, and urea-formaldehyde and crosslinked polyepoxides and polyesters, as described in US Pat. No. 3,070,510, issued Dec. 15, 1962. Preferred abrasives include crystalline silica, silica gel or colloidal silica and complex amorphous alkali metal aluminosilicates having a particle size of about 5 microns or less, an average particle size of about 1.1 microns or less, and a surface area of about 50,000 cm 2 / gm. .

When visually transparent gels are used, abrasives of colloidal silica, alkali metals, such as those sold under the trade names Siloid, such as Syloid 72 and Siloid 74, or under the trade name Santocel, such as Santocel 100 Aluminosilicate complexes are particularly useful because they have a refractive index close to that of the gelling-liquid (including water and / or moisturizing) systems commonly used in toothpastes.

Many so-called water-insoluble abrasives are anionic and also contain small amounts of solubles. Thus, insoluble sodium metaphosphate may be formed in any suitable manner illustrated by the torpedo dictionary of applied chemistry (Vol. 9, 4th edition, p 510-511). Insoluble sodium metaphosphate forms known as Madrell's salts and Kurrol's salts are another example of a suitable material. Such metaphosphate salts exhibit only minor solubility in water and are therefore commonly referred to as insoluble metaphosphate (IMP). As excitation impurities, small amounts of soluble phosphate material generally up to 4% by weight are present. In the case of insoluble metaphosphates, the amount of soluble phosphate material, which is believed to include soluble sodium trimetaphosphate, can be reduced or eliminated by washing with water if desired. Insoluble alkali metal metaphosphates are typically used in the form of powders with particle sizes of only 1% of material greater than 37μ.

The abrasive is present in the composition, such as a solid or a paste, at a concentration of about 10 to about 99 weight percent. It is preferably present in about 10% to about 75% in the cream dentifrice, and about 70% to about 99% in the powder dentifrice. In the case of cream toothpastes, when the abrasive is actually silicic acid it is usually present in about 10 to 30% by weight. Other abrasives are typically present at about 30-75 weight percent.

In the case of cream dentifrices, the liquid excipient may typically include water and a humectant in an amount of about 10 to about 80 weight percent of the formulation. Glycerin, propylene glycol, sorbitol and polypropylene glycol are examples of suitable moisturizers / carriers. Also advantageous are liquid mixtures of water, glycerin and sorbitol. For clear gels in which refractive indices are of great importance, about 2.5 to 30% by weight of water, 0 to about 70% by weight of glycerine and about 20 to 80% by weight of sorbitol are preferably used.

Toothpastes, creams and gels typically contain natural or synthetic thickeners or gelling agents in a ratio of about 0.1 to about 10%, preferably about 0.5 to about 5%. Suitable thickeners are synthetic colloidal magnesium alkaline metal silicate composite clays and synthetic hectorides available as Laponite (eg CP, SP2002, D) sold by Laforte Industries Limited. Laponite D analysis shows approximately 58.00 wt% SiO ₂ , 25.40 wt% MgO, 3.05 wt% Na ₂ O, 0.98 wt% Li ₂ O, and some water and trace amounts of metal. Its actual specific gravity is 2.53 and has an apparent bulk density (g / ml at 8% moisture) of 1.0.

Other suitable thickeners are Irish moss, iota carrageenan, gum tragacanth, starch, polyvinylpyrrolidone, hydroxyethylpropylcellulose, hydroxybutyl methyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose (e.g. nats Commercially available as rosol), sodium carboxymethyl cellulose, and colloidal silica such as finely ground siloids (eg, 244). In particular, when at least about 0.35% by weight of the water insoluble antimicrobial agent is used and the silicate abrasive is present at less than about 30% by weight, it will be desirable to include agents that dissolve the antimicrobial agent in some toothpastes made in accordance with the present invention. The solubilizers include vegetable oils containing at least about 12 carbons in straight chains such as cellulose glycols, moisturizing polyols such as propylene glycol, dipropylene glycol and hexylene glycol, cellosolves such as methyl cellosolve and ethyl cellosolve, olive oil, castor oil and petroleum; Waxes, and esters such as amyl acetate, ethyl acetate and benzylbenzoate.

It will be commonly understood that oral formulations will be sold or dispensed in suitably labeled packages. Thus, the salvage liquor jar will be labeled substantially as salvage liquor or salvage liquor and labeled with instructions for its use; A cream toothpaste, cream or gel is a collapsible tube, or other squeeze, pump or pressurized, typically aluminum, lined lead or plastic, for shipping the contents substantially labeled as a cream toothpaste, gel or dental cream Will be put into the dispenser.

Organic surfactants are used in the compositions of the present invention to obtain increased preventive action, to achieve a thorough and complete dispersion of antiplaque and antibacterial agents through the oral cavity, and to make the composition more superficially acceptable. The organic interfacial-active material is preferably essentially an anionic, nonionic or amphoteric electrolyte, and it is preferable to use a cleaning material as the surfactant, which imparts cleaning and foaming properties to the composition. Suitable examples of anionic surfactants are water-soluble salts of higher fatty acid monoglyceride monosulfates, such as sodium salts of monosulfated monoglycerides of hydrogenated coconut oil fatty acids, higher alkyl sulfates such as sodium lauryl sulfate, sodium dodecyl Lower aliphatic, such as alkyl arylsulfonates such as benzyl sulfonate, higher alkyl sulfoacetates, higher fatty acid esters of 1,2-dihydroxy propane sulfonate, and those having 12 to 16 carbons in the fatty acid, alkyl or acyl radicals There is a fairly saturated higher aliphatic acyl amide of the amino carboxylic acid compounds. Examples of the amides mentioned at the end are the sodium, potassium and ethanolamine salts of N-lauroyl, N-myristoyl, or N-palmitoyl sarcosine and N- which must be essentially free of soap or similar higher fatty acid substances. There is lauroyl sarcosine. The use of such sarcosinate compounds in the oral compositions of the present invention not only slightly reduces the solubility of tooth enamel in acid solutions but also has a profound effect on prolonged inhibition of oral acid formation due to carbohydrate degradation. It is particularly advantageous because it is shown. Examples of water soluble nonionic surfactants include condensation products of various reactive hydrogen-containing compounds with long hydrophobic chains (such as aliphatic chains of about 12 to 20 carbon atoms) and ethylene oxide, where the condensation product (ethoxamers )) Is water-soluble, such as condensation products of fatty acids, fatty alcohols, fatty amides, polyhydric alcohols (e.g. sorbitan monostearate) and polypropylene oxides (e.g. Pluronic substances) and poly (ethylene oxide) Polyoxyethylene moiety.

The surfactant is typically present in an amount of about 0.1 to 5% by weight, preferably about 1 to 2.5% by weight. It is noteworthy that the surfactant can reduce the amount of dissolution required of the moisturizer by assisting the dissolution of the non-cationic antimicrobial agent.

Various other materials may be incorporated into the oral formulations of the present invention, such as bleaches, preservatives, silicones, chlorophyll compounds and / or ammonialated materials such as urea, diammonium phosphate, and mixtures thereof. When present, these auxiliaries are incorporated into the formulations in amounts that do not essentially adversely affect the desired properties and properties. Significant amounts of zinc, magnesium and other metal salts and materials that are generally soluble and complex with the active ingredients of the present invention should be avoided.

Any suitable flavor or sweetening material may also be used. Examples of suitable flavor ingredients include flavor oils such as spearmint, peppermint, wintergreen, sasfrafras, clove, sage, euclyptus, majoram, Cinnamon, lemon, and orange oils, and methyl silicates. Suitable sweeteners include sucrose, lactose, maltose, sorbitol, xylitol, sodium cyclamate, peryllatin, AMP (aspartylphenylalanine, methyl ester), saccharin and the like. Suitably, the flavor and sweetener may each or together constitute about 0.1-5% or more of the formulation. In addition, flavor oils seem to aid in dissolution of the antimicrobial agent.

In a preferred embodiment of the present invention, the oral composition according to the present invention, such as a cleaning solution or toothpaste containing the composition of the present invention, has a pH of about 4.5 to about 9, generally about 5.5 to about 8, preferably about 6 to 8 It is preferred to apply regularly, such as at least two to eight weeks or longer to lifetime, daily or every other day or every three days or preferably one to three times a day.

The compositions of the present invention may, for example, refer to gum bases (such as Jelutdong, rubber latex, vinyllite resins, etc.), preferably as conventional plasticizers or emollients, sugars or other sweetening agents such as glucose, sorbitol and the like. It may be incorporated into lozenges, or gums or other products by coating the outer surface of.) Or by stirring in a hot gum base.

It is understood that the following examples further illustrate, but are not limited to, the nature of the present invention. All amounts and proportions mentioned in this application and in the appended claims are by weight unless otherwise indicated.

In the examples below, the 2,4,4-trichloro-2'-hydroxydiphenyl ether, which is a pharmaceutical trigloic acid, is indicated as TCHE; Sodium lauryl sulfate is indicated as SLS; Copolymers of maleic anhydride and methyl vinyl ether, available from GAF Corporation as Gantrez S-97, are identified as Gantrez; Tetrasodium pyrophosphate is identified as pyrophosphate; Sodium fluoride is identified as NaF.

Example 1

Release of reagents from dental minerals for anti-plaque / anti-tartar effects by antimicrobial adsorption to saliva-coated tooth mineral hydroxyapatite discs in the presence of pyrophosphate and different amounts of polycarboxylates Adsorption to tooth minerals was analyzed.

The evaluated cream toothpaste formulations are as follows:

Gantrez is present as A.I. in an amount of 2.0 parts in Cream Toothpaste B in 2.5 parts in Cream Toothpaste A.

To test the delivery of the antimicrobial agent to the saliva coated hydroxyapatite disc, hydroxystatatide (HA) obtained from Monsanto Company was washed with distilled water, collected by vacuum filtration and dried at 37 ° C. overnight. I was. The dried HA was ground into a powder with a mortar and pestle. 150.00 mg of HA was placed in a chamber of KBr pellet die (Barnes Analytical, Standford, CT) and pressed for 6 minutes at 10,000 pounds in a Garber laboratory press. The resulting 13 mm disc is sintered at 800 ° C. for 4 hours in a Thermolyne furance. The entire parafilm stimulated saliva is collected in an ice cooled glass beaker. Saliva is cleared by centrifugation at 15,000 Xg (time gravity) at 4 ° C. for 15 minutes. The sample is sterilized by irradiation with UV rays for 1.0 hour and stirred to sterilize the cleared saliva at 4 ° C.

Each sintered disc is hydrated with sterile water in a polyethylene test tube. The water is then removed and replaced with 2.00 ml of saliva. The disks are incubated overnight at 37 ° C. with continuous stirring in the water bath to form a saliva thin film. After the treatment, saliva is removed, the disc is treated with 1.00 ml of a solution (triclosan) containing antimicrobial agent in the toothpaste liquid solution, and incubated at 37 ° C while stirring in a water bath. After 30 minutes, transfer the disk to a new tube, add 5.00 ml of water and gently stir the disk with vortex. Then transfer the disc to a new tube and repeat the cleaning process twice. Finally, the disc is carefully transferred to a new tube so that no liquid is co-transfered along the disc. Then 1.00 ml of methanol is added to the disk and vigorously shaken with vortex. The sample is placed at room temperature for 30 minutes to extract the triclosan absorbed in methanol. Methanol is then aspirated and clarified by centrifugation at 10,000 rpm for 5 minutes in a Beckman microfuse. After this treatment, methanol is transferred to HPLC (high performance liquid chromatography) vials to determine the antimicrobial concentration. Three samples are used for all tests.

The data is summarized in the table below.

The data show that with an increase in the amount of gantretz (cream toothpaste A), there is a very large increase in TCHE delivery to saliva coated tooth minerals.

Example 2

The following toothpastes are effective as anti-plaque and anti-stone compositions:

Example 3

Example 4

Example 5

Example 6

In this example, replace TCHE with phenol, 2,2'-methylene bis (4-chloro-6-bromophenol), eugenol and thymol respectively and / or replace Gantrez with carbopol (such as 934), or poly Styrene phosphonic acid polymers having a molecular weight ranging from about 3,000 to 10,000, such as (beta-styrenephosphonic acid), copolymers of vinyl phosphonic acid with beta-styrene phosphonic acid, and poly (alpha-styrenephosphonic acid), or sulfo Improved results can also be obtained when replacing with another AEA, such as a 1: 1 copolymer of acrylic acid oligomer or maleic anhydride with ethyl acrylate.

Similarly, the weight ratio of potassium to sodium is a) 0.37: 1 b) 1.04: 1; c: 3: 1; And 3.5: 1 similar results are obtained when replacing pyrophosphate (tetrasodium pyrophosphate) with tetrasodium pyrophosphate and tetrapotassium pyrophosphate.

The present invention has been described with respect to certain preferred embodiments, and it will be understood that modifications and variations apparent to those skilled in the art are included within the scope of the present application and the appended claims.

Claims (24)

In an orally acceptable excipient, 0.1 to 3% by weight of one or more linear molecularly dehydrated polyphosphate salts as anti-calculators, 0.01 to 5% by weight of substantially water-insoluble noncationic antimicrobials, and Comprising up to 4% by weight of an antimicrobial-enhancer containing at least one delivery-enhancing functional group and at least one organic retention-enhancing group to enhance delivery to and oral retention on the surface of the oral cavity, wherein the antimicrobial enhancer to polyphosphate ion Oral composition having a weight ratio of 1.6: 1 to 2.7: 1. The oral composition of claim 1, wherein the antimicrobial agent is selected from the group consisting of halogenated diphenyl ethers, halogenated salicylates, benzoic acid esters, halogenated carbanilides, and phenolic compounds. The oral composition of claim 1, wherein the antimicrobial agent is a halogenated diphenyl ether. 4. The oral composition of claim 3, wherein the halogenated diphenyl ether is 2,4,4'-trichloro-2'-hydroxyphenyl ether. The oral composition according to claim 2, wherein the amount of antimicrobial agent is 0.25 to 0.5% by weight. The oral composition of claim 1, wherein the linear molecularly dehydrated polyphosphate salt is an alkali metal pyrophosphate present in an amount of 1 to 2.5 wt%. 7. The oral composition of claim 6, wherein the alkali metal pyrophosphate is tetrasodium pyrophosphate. The oral composition of claim 1, wherein the weight ratio of antimicrobial enhancer to polyphosphate ion is from 1.7: 1 to 2.3: 1. The oral composition of claim 1, wherein the excipient is water, a moisturizer, and a gelling agent, and the oral composition is a toothpaste comprising an acceptable water-insoluble abrasive for teeth. The oral composition of claim 1, wherein the excipient consists of water and a non-toxic alcohol and the oral composition is a salvage solution. The oral composition of claim 1, wherein the antimicrobial-enhancing agent has an average molecular weight of 1000 to 1,000,000. The process according to claim 4, wherein the delivery-enhancer is selected from the group consisting of carboxylic acids, phosphonic acids, phosphinic acids and sulfonic acids and salts thereof and mixtures thereof, wherein the organic retention-enhancer is a general formula (X) _n -R wherein , X is O, N, S, SO, SO ₂ , PO or Si, R is hydrophobic alkyl, aryl, alkenyl, acyl, alkaryl, aralkyl, heterocyclic or inactive-substituted derivatives thereof, n is 1 or 0). 13. The oral composition of claim 12, wherein the antimicrobial-enhancing agent is an anionic polymer containing a plurality of delivery-enhancers and organic retention-enhancers. The oral composition of claim 13, wherein the anionic polymer consists of chains containing repeat units each containing one or more carbon atoms. 15. The oral composition of claim 14, wherein each unit contains one or more organic retention-enhancers and one or more delivery-enhancers bonded to the same, proximal or different atoms in the chain. 13. The oral composition of claim 12, wherein the delivery-enhancing group consists of carboxylic acid groups or salts thereof. 17. The oral composition of claim 16, wherein the antimicrobial-enhancing agent is a copolymer of maleic acid or maleic anhydride with another ethylenically unsaturated polymerizable monomer or salts thereof. 18. The oral composition according to claim 17, wherein the other monomer is methyl vinyl ether having a molar ratio of maleic acid or maleic anhydride of 4: 1 to 1: 4. 19. The oral composition of claim 18, wherein the copolymer has a molecular weight of 30,000 to 1,000,000. The composition of claim 19 wherein the copolymer has an average molecular weight of 70,000. The composition of claim 12, wherein the delivery-enhancing group consists of a phosphonic acid group or salts thereof. 22. The method of claim 21 wherein the antimicrobial-enhancing agent is a copolymer of poly (β-styrenephosphonic acid), poly (α-styrenephosphonic acid) or styrenephosphonic acid with the remainder or other inert polymerizable ethylenically unsaturated monomers or salts thereof. Chain composition. The composition of claim 22 wherein the antimicrobial-enhancer has a molecular weight of 1,000 to 30,000. 24. The oral composition according to any one of claims 1 to 23, containing a fluoride ion-providing source.